In this proposal, we will investigate the role of adventitia-derived superoxide O2 in vascular reactivity, hypertrophy and injury response in hypertension. The proposal stems from our previous findings (a) documenting expression of phagocyte-like NADPH oxidase components in the adventitia of arteries: (b) demonstrating that this enzyme is the major source of vascular O2 (C) demonstrating that p67Ph0x. a critical component in phagocyte NADPH oxidase activity is essential to vascular oxidase activity: (d) showing that AngII-induced elevation of vascular O2 is associated with transcriptional activation of adventitial NADPH oxidase: and (e) demonstrating that now el inhibitors of this enzyme attenuate AngII-induced O2 production. While our data have established the presence of a vascular NADPH oxidase source of O2 and revealed some of its molecular character. little is known of its regulation, or the significance of its location in the adventitia. We will address tine physiological significance of NADPH oxidase by testing tine hypothesis that increased vascular levels of O2 via adventitial NADPH oxidase expression and assembly of its components during the development of AngII-dependent hypertension impair endothelium-dependent responses. and enhance the medial in hypertrophic response and neointimal proliferative response to injury, in testing this hypothesis. we will (1) examine a variety of cell-permeant chimeric peptide sequences that we developed as to their effectiveness in blocking assembly of the oxidase, vascular O2 generation, and attenuating AngII-dependent blood pressure elevation: (2) target these NADPH oxidase inhibitors to various vascular cell types by adenoviral transfection and development of a transgenic mouse model and examine tine effect on endothelium-dependent responses: (3) examine the effect of cell targeting on medial hypertrophy. and compare responses in glutathione peroxidase-l-deficient versus wild-type mice (4) examine the effect of cell targeting on mvofibroblast migration and neointimal proliferation during the vascular injury response.